The principal objective of the proposed research is to develop a fundamental understanding of the actions of autonomic agents and cyclic nucleotides on the inflammatory process. One important cellular mediated phase of inflammation will be studied, namely, the extracellular release of cartilage-degrading and other lysosomal enzymes from human neutrophils in the presence of immunologic rectants. The proposed research is directed along four specific aims: 1) development of a suitable cellular model whereby contact of neutrophils with cartilage and immunologic reactants provokes lysosomal enzyme release and concomitant cartilage degradation without loss of cell viability; 2) elucidation of the pharmacologic actions of adrenergic and cholinergic agents as well as adenosine 3', 5'-cyclic monophosphate (cyclic AMP) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) on release of lysosomal enzymes from neutrophils; 3) measurement of neutrophil concentrations of cyclic AMP and cyclic GMP during cell contact with immunologic reactants and autonomic agents; 4) identification and isolation of specific cyclic nucleotide-dependent protein kinases enzymes that might mediate the cellular actions of cyclic nucleotides via phosphorylation of appropriate cellular components. Each of these approaches should contribute to the achievemnet of the objective and attainment of the overall goal of these and related studies, namely, the development of clinically effective anti-inflammatory drugs for the treatment of rheumatoid arthritis and associated health disorders.